Among the most pressing global public health problems at present is the AIDS epidemic. While it is clear that chemotherapy and behavioral interventions have much to offer in limiting the spread of infections by the causative virus, HIV-1, interest in developing a vaccine remains strong. Immunization would potentially provide a relatively cost-effective and scalable approach to minimizing the incidence of new infections on a global scale.
However, HIV-1 presents numerous challenges to would-be vaccine developers. There are many different lineages of HIV-1 viruses with different clades dominating in different geographic regions of the world. Even in a single infected patient, HIV-1 continues to generate many variants. Astonishingly, according to Korber et al. (2001), “The diversity of influenza sequences world-wide in any given year appears to be roughly comparable to the diversity of HIV sequences found within a single infected individual at one time point ….” The virion surface protein, gp120, which is critically involved in infecting host cells and is a major target for protective antibodies, contains regions that are especially variable in amino acid sequence.
In addition to the serious challenge of eliciting an immune response, of whatever sort, that can effectively provide immunity to the many viral variants in circulation, it remains unclear what types of immune responses are essential for providing a high level of protection against infection or disease. Some investigators are focsed on eliciting strong cell-mediated immune response. Others are devoting their efforts to generating humoral responses including potent and broadly-neutralizing antibodies. There are several recent and interesting reports pertaining to this latter effort.
In the September 16, 2011, issue of Science, Wu et al. and Scheid et al. independently characterize antibody responses in individuals infected with HIV-1 who have generated serum antibodies that potently neutralize HIV-1 strains exhibiting highly diverse amino acid sequences, so-called broadly-neutralizing antibodies. Using high-throughput nucleotide sequencing of expressed heavy and light chain variable domains, Wu et al. and to a lesser extent Scheid et al. analyzed the somatic evolutionary process that leads to broadly-neutralizing antibodies.
Wu et al. find that the antibodies able to bind to HIV-1 gp120 and effectively neutralize viruses from many different lineages exhibit two to for times as many somatic mutations as is typically seen in antibodies to other antigens. Their results add to the data favoring the hypothesis that enormous numbers of somatic mutations in germline heavy and light chain variable are necessary, at least in many cases, for antibodies to attain the ability to bind tightly to HIV-1 gp120 and potently neutralize viruses exhibiting substantially divergent amino acid sequences. The results of Scheid et al. are also consistent with this conclusion. Thus, to the extent that the humoral response can confer protection against HIV-1, the host depends on extensive evolutionary diversification of immunoglobulin genes in B lymphocytes to effectively combat the evolutionary diversification of the virus. Furthermore, processes (i.e., replication of DNA or RNA) that at high resolution can be regarded as generating errors are in this context of a dynamic molecular-level contest a source of strength without which defeat, in evolutionary terms, would inevitable.
In the issue of Nature (September 22, 2011) published the week after the papers by Wu et al. and Scheid et al., Walker et al. generated monoclonal antibodies from four individuals infected with HIV-1 whose sera exhibited potent and broad HIV-1-neutralizing activity. A few of the resulting monoclonal antibodies exhibited neutralization potencies 100-fold better than some of the first-described broadly neutralizing human monoclonal antibodies (such as b12, 2G12, and 4E10) and roughly 10-fold better than some more recently-described broadly-neutralizing monoclonal antibodies, such as PG9, VRC01, and PGV04. The authors argue that combinations of these most-recently described monoclonal antibodies (e.g., PGT128 and PGT 145), with complementary (i.e., usefully non-overlapping) neutralization patterns, might cover a substantial proportion of all circulating HIV-1 strains at plausible serum antibody concentrations.
Finally, this month, Pejchal et al. (Science, 2011) have published a detailed analysis of the molecular basis for the binding and neutraliziation activities of the two of the monoclonal antibodies inititially characterized in the paper by Walker et al., PGT 128 and PGT 127. The authors note that HIV-1 employs several evolutionary strategies to evade immune mechanisms, including, amino acid sequence variability of the viral surface proteins, steric constraints pertaining to relatively conserved polypeptide sequences, and extensive glycosylation to impede accessibility to portions of viral surface proteins that might otherwise serve as likely targets for antibody binding. PGT 128 (the antibody with the broadest neutralization profile of the PGT series antibodies) and PGT 127 have “solved” some of the challenges presented by HIV by virtue of their abilities to bind simultaneously to both of two relatively well-conserved glycan substituents of gp120 and one protion of the polypeptide backbone in the V3 loop. It appears that an insertion the second heavy chain hypervariable region greatly enhances the interactions of these two antibodies with one of the two contacted glycans.
These results raise a number of intriguing questions. Why do only 30% or fewer of individuals infected with HIV-1 generate broadly neutralizing serum antibody responses to HIV-1 antigens? Do genetic vartiants at immunoglobulin or other loci influence the likelihood of the development of broadly neutralizing serum antibody responses? Why does it take two to three years for such responses to develop? Can vaccine immunogens be designed to elicit such responses with a high probability in most potential vaccine recipients, as is implicitly assumed by the ionvestigators pursuing studies focused on extensive characterization of the potent and broadly neutralizing antibodies? What role do stochastic processes play in the evolution of B lymphocytes secreting potent broadly neutralizing antibodies? Does prior antigenic experience influence the probability of developing a potent and broadly neutralizing serum antibody response? Does the magnitude and specificity of the cell-mediated immune response to HIV-1 influence the magnitude and quality of the humoral immune response to the virus, or vice versa? What role do differences in the infecting genome or genomes play in influencing the magnitude and quality of the humoral immune response to the virus?
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